LncRNAs-associated to genomic instability: A barrier to cancer therapy effectiveness

Abstract

Although a large part of the genome is transcribed, only 1.9% has a protein-coding potential; most of the transcripts are non-coding RNAs such as snRNAs, tRNAs, and rRNAs that participate in mRNA processing and translation. In addition, there are small RNAs with a regulatory role, such as siRNAs, miRNAs, and piRNAs. Finally, the long non-coding RNAs (lncRNAs) are transcripts of more than 200 bp that can positively and negatively regulate gene expression (both in cis and trans), serve as a scaffold for protein recruitment, and control nuclear architecture, among other functions. An essential process regulated by lncRNAs is genome stability. LncRNAs regulate genes associated with DNA repair and chromosome segregation; they are also directly involved in the maintenance of telomeres and have recently been associated with the activity of the centromeres. In cancer, many alterations in lncRNAs have been found to promote genomic instability, which is a hallmark of cancer and is associated with resistance to chemotherapy. In this review, we analyze the most recent findings of lncRNA alterations in cancer, their relevance in genomic instability, and their impact on the resistance of tumor cells to anticancer therapy.

Keywords: CONCR; NORAD; cancer therapy; genomic instablity; lncRNAs.

FIGURE 1

NORAD is involved in the proper segregation of chromosomes. Two mechanisms by which NORAD promotes chromosome segregation have been proposed. First (above), NORAD negatively regulates PUM1 and PUM2 proteins allowing the expression of genes involved in cell cycle processes. On the other hand, NORAD forms a ribonucleoprotein complex with the RBMX protein, where they have a role in DNA duplication and repair. However, it is not clear how this function participates in chromosome segregation.

FIGURE 2

Mechanisms proposed to mediate the relationship between RNAs transcribed from the centromere and pericentromere and treatment response. Upper right panel: etoposide promotes DNA double-strand breaks (DSBs) through its interaction with topoisomerase 2 A (TOP2A) and the formation of a ternary complex with the DNA. Etoposide-induced satellite III RNAs participate in sequestering TOP2A in nuclear stress bodies, which prevents the generation of DNA DSBs. Lower right panel: Proteasome inhibition by bortezomib (used in treating multiple myeloma, among other malignancies) promotes cell death through proteolytic stress and a prolonged mitotic, followed by cohesion fatigue (among other mechanisms). Upon bortezomib treatment, delayed mitotic progression is associated with the overexpression of α-satellite RNAs. These transcripts interact with cohesin subunits, which could inhibit the establishment of cohesion fatigue. On the other hand, the expression of satellite III RNAs in mesenchymal stromal cells (associated with B-lymphocytes in the bone marrow) triggered by bortezomib has been shown to protect malignant B cells (the target of bortezomib) from bortezomib toxicity. DSB: Double Strand Breaks. MSC: Mesenchymal Stromal Cell.

FIGURE 3

The telomeres in eukaryotic cells protect the extremes of the linear chromosomes. Note that the canonical telomeric sequence (5′-TTAGGG-3′) degenerates into associated repeats towards the chromosome sequence. The lncRNA TERRA forms R-Loops in the telomeric tract to increase telomere protection. Still, a potential therapeutic application can derive from R-Loop accumulation by inducing senescence/apoptosis. hTERT + tumor cells treated with 5-azacytidine or trichostatin will increase TERRA transcription; ALT + tumor cells treated with RNHIs will not be able to dismantle DNA/RNA hybrids. Both treatments can lead to telomeric R-Loop accumulation, DNA damage, telomere shortening, and arresting cell division.

FIGURE 4

lncRNAs participate in the p53 pathway downstream and upstream of p53. Four lncRNAs are depicted relative to p53, along with the identified consequences of their expression (green arrows) or repression (red arrows), be it experimental or naturally occurring in cancer.